Method to produce roentgenographic pictures and composition for realization of the method



United States Patent 3,340,151 METHOD TO PRODUCE ROENTGENOGRAPHIC PICTURES AND COIVIPOSITION FOR REALIZA- TION OF THE METHOD Sven Axel Eriksson, Sodertalje, Max Fischler, Hagersten,

and Ake Samuel Gidlund, Djursholm, Sweden, assignors to Aktiebolaget Astra Apotekarnes Kemiska Fabriker, Sodertalje, Sweden No Drawing. Filed May 22, 1964, Ser. No. 369,580 9 Claims. (Cl. 167-66) This invention relates to compositions having utility in X-ray examination of the gall bladder and its ducts.

In X-ray examination of the gall bladder it has not hitherto been usual to cause contraction of the gall bladder so as to make the bile ducts visible also, since no sufficiently effective agent capable of causing a rapid gallevacuation has been available. In order to make sure that no stones remain in the bile ducts when the gall bladder has been removed it has instead been necessary to resort to other methods of examination. Thus one may carry out palpation of the bile ducts in order to feel if any stones remain therein. This method has, however, the disadvantage that thick walls of the bile ducts may prevent the detection of possible stones or that the bile duct as a whole may not be within reach. An alternative is to liberate the bile duct during the operation and to introduce a solution of an X-ray contrast medium by a catheter into the bile duct and make a radiograph. This method prolongs the operation considerably and involves greater risks for the patient. A normal gall-stone operation lasts between 25 and 45 minutes, while such an extra X-ray examination of the bile ducts requires about 30 minutes more. As in this method it is necessary to make the narcosis considerably longer, and also more intense at the end of the operation, the toxic action of the narcotic becomes greater than necessary, with accompanying stronger after-effects and greater risks for the patient. If, on the other hand, it were possible pre-operatively, a short time after the first X-ray examination of the gall, to cause a gall-evacuation, the following advantages should be attained.

(1) The need of an extra examination of the bile ducts during the operation would be eliminated since the X-ray contrast medium would be forced by the contraction of the gall bladder to the bile ducts, which will then be made visible, any stones being shown on an X-ray plate. If the bile-duct is completely obstructed, a portion of the contrast medium would flow only partly into the ducts at the evacuation of the gall bladder, and this also would be observed on the plate.

(2) Any infections in the walls of the gall bladder, not related to concrements, would immediately be discovered, since in these cases the contraction of the gall bladder would be reduced or fail to appear while no stones would be observed on the X-ray plate.

At present about 15% of all patients operated on for gallstones have to be brought back to hospital for a further operation, for the reason that stones in the bile ducts have not been discovered during the operation. The serious attacks of jaundice caused by this, which demand immediate operation, could be eliminated beforehand if an effective examination by evacuating the gall bladder could be carried out.

Owing to these advantages of examinations with evacuation of the gall bladder, egg-meals have been used to cause contraction. The time between an eg -meal and a complete evacuation of the gall is, however, as long as 2.5-3 hours, for which reason it has not been feasible to use this method in practice. Owing to the heavy load on the majority of X-ray departments, only about 20 minutes can be allowed between the ingestion of a composition and complete evacuation of the gall bladder.

3,3405151 Patented Sept. 5, 1967 The present invention provides a composition whose use makes possible pre-operative X-ray photography of the bile ducts and the contracted gall bladder a very short time after the first picture has been taken, by which the advantages described above as resulting from a rapid and complete evacuation of the gall bladder are attained. More particularly the invention provides an orally administrable composition which causes some contraction of the gall bladder as little as 5 minutes after ingestion and complete evacuation of the gall bladder in about 15 minutes.

The compositions of the invention comprise as active components a hexitol, a non-toxic ester or ether of a polyalkylene glycol or a polyoxyalkylene adduct, and a solid or liquid animal or vegetable edible fat. (By polyoxyalkylene adduct we mean a compound obtained by the reaction of a number of molecules of an alkylene oxide with a compound capable of forming an ester or ether linkage with the polyoxyalkylene chain so produced.) In use such a composition is administered orally after a conventional composition to render the gall bladder visible, and a series of X-ray photographs are taken. Suitably the contraction of the gall bladder is followed r0- entgenographically from the non-contracted to the maximally contracted state by a small number of exposures. For instance the first may be made immediately before the intake of the gall bladder contracting composition followed by two others 5 and 15 minutes after the intake respectively.

Suitable hexitols for use in the gall bladder contracting compositions are for instance sorbital, mannitol, dulcitol and iditol. Of these sorbitol and mannitol are the most easily available and of these sorbitol is especially suitable owing to its solubility properties.

Suitable polyethylene glycol adducts are: among the esters for instance polyethylene glycol stearate (Myrj), among the ethers, for instance polyethylene glycol lauryl ethers (Brij) and among other polyethylene glycol adducts for instance polyethylene glycol sorbitan esters, such as monooleate, monostearate, monopalrnitate and trioleate thereof (Tween). Especially preferred among the polyoxyethylene products are polyethylene glycol 'sorbitan monooleate (Tween and polyethylene glycol stearate (Myrj 51).

As examples of suitable fats to be included in the gall bladder contracting compositions may be mentioned peanut oil, soya bean oil, cotton-seed oil, castor oil, linseed oil, rape-seed oil, olive oil, sesame oil, coconut oil, palm oil, anise oil, fish oils, cocoa-butter and coconut butter. Of these peanut oil has been found especially suitable.

The compositions of the invention are preferably administered in liquid form, with the active components dissolved or dispersed in water together with conventional additives such as fiavouring agents, preserving agents, stabilizing agents etc., but it is also possible to administer them in the solid form, ie without water, although contraction then is somewhat delayed owing to the time needed for the breaking up of the solid composition and the dispersion or solution of the solid components. This disadvantage may be diminished by the addition of disintegrating agents such for instance as sodium bicarbonate in combination with tartaric acid, calcium citrate etc.

When the composition is in the liquid form the active ingredients are preferably in an extremely finely dispersed form, preferably in colloidal solution, that is with a particle size less than 0.1 since compositions of greater particle size are resorbed too slowly for the quickest action.

Examples of preserving agents which may be included in the composition to prevent the growth of micro-organ- 3 isms are propyl-p-hydroxybenzoic acid (Nipasol), salicylic acid and sorbic acid.

Examples of suitable stabilizing agents are complexforming substances or stabilizers such for example as ascorbic acid (a typical anti-oxidant), and citric acid, ethylenediaminotetra-acetic acid, or citraconic acid (complex-forming substances).

Suitable flavouring agents are sweeteners such as saccharin sodium, sodium cyclamate, sodium glutamate and flavouring essences such as orange essence, etc.

From the point of view of taste and also of resistance to micro-organisms the pH of the liquid composition is preferably about 2-5.

The amounts of the active components in the gall bladder-contracting composition may be varied within wide limits; for instance the amount of the hexitol will depend partly on its solubility properties. From the point of view of effectiveness and taste the hexitol content of the liquid composition is preferably 10-70 parts, the amount of polyalkylene glycol ester or ether or polyoxyalkylene adduct 2-1 5 parts, and the amount of fat 0.1-l.5 parts, all per 100 parts of water. (All parts are by weight.) Specially suitable are compositions containing 25-35 parts hexitol, 6-10 parts polyalkylene glycol ester or ether or polyoxyalkylene adduct, and 0.2-0.7 part of fat per 100 parts of water.

When the gall bladder-contracting composition is to be administered in solid form, the amount of hexitol is preferably 25-70%, the amount of polyalkylene glycolester or ether or polyoxyalkylene adduct 25-70%, and the amount of fat 1-7% of the weight of the composition. Specially suitable are compositions containing 35-60% of hexitol, 35-60% of polyalkylene glycol ester or ether or polyoxyalkylene adduct, and 2-6% of fat.

The invention is illustrated by the following examples, which are however, not intended to limit it. The parts are by weight.

The polyethylene glycol sorbitan monooleate was heated to 50 C., after which the peanut oil and the water-soluble flavoun'ng agents were added with continuous stirring at 50 C. The resulting solution was allowed to cool to 30 C., when an aqueous solution containing the watersoluble flavouring agents and V of the amount of sorbitol was incorporated with stirring. When a clear solution had been obtained the remaining sorbitol was added with stirring at a temperature of -30 C., after which the resulting solution was diluted to a volume of 100 ml. and the pH was adjusted to 4.5.

Example II In the same manner as in Example I a solution was prepared from the following ingredients:

The polyethylene glycol stearate was melted at 4050 C. The peanut oil and the flavouring agents and the colourants were dissolved in the melt, after which the sorbitol was mixed in and the resulting mixture was moulded into tablets.

Example IV In the same manner as in Example III solid tablets of the following composition were prepared:

Parts Maunitol 2.60 Polyethylene glycol stearate (Myrj 51) 2.60 Peanut oil 0.15 Flavouring agents 0.40 Colourants 0.001

The liquid compositions are suitably administered in such an amount that as much as possible of the intestine mucosa is covered with the gall-emptying composition. Suflicient effect is obtained at a dose of about 50 ml., but it may in certain cases be preferable to use a double dose, and this can be swallowed by the patient without difficulty.

The toxicity of the gall bladder contracting compositions is so small that it cannot be determined. Tests performed in mice show an oral LD 50 greater than 50 g./ kg. mouse.

In comparable tests in the same person with compositions containing only one or two of the active ingredients, acceptable times (50 minutes or less) of emptying of the gall bladder have not been obtainable; thus a synergistic effect is concerned, which is forthcoming only when the three components are present at the same time in suitable proportions.

What we claim is:

1. A method for contracting the gall bladder for X-ray diagnosis which comprises administering orally an effective dose of a composition consisting essentially of, as its active constituents, (a) a material of the [group consisting of sorbitol and mannitol, (b) a material of the group consisting of nontoxic water-dispersible polyethylene glycol esters and ethers containing at least about 5 oxyethylene groups per molecule, of the class consisting of (1) polyethylene glycol esters of higher fatty'acids, (2) polyethylene glycol ethers of higher fatty alcohols, and (3) polyoxyethylene derivatives of cyclized 'hexitols esterified with higher fatty acids, and (c) a material of the :group consisting of solid and liquid animal and vegetable edible fats, said constituents being dispersed in water, said constituents being within the limits of 10 to parts by weight of sorbitol and mannitol, 2 to 115 parts by weight of said polyethylene glycol esters or ethers, or polyoxyethylene derivatives, and 0.1 to 1.5 parts by weight of the fat, per parts of water.

2. The method according to claim 1 wherein said component (b) is a polyethylene glycol ester of a higher fatty acid.

3. The method according to claim 1 wherein said component (b) is polyoxyethylene derivative of a cyclized hexitol esterified with the higher fatty acid.

4. The method according to claim 1 wherein the particle size of said dispersed constituents is below 0.1 micron.

5. The method according to claim 1 wherein said composition has a pH of 2 to 5.

6. The method according to claim 1 ,wherein the amount of said material (a) is 25 to 35 parts, the amount of said material (13) is 6 to 10 parts, and the amount of 5 said material (c) is 0.2 to 0.7 part per 100 parts 'of water.

7. The method according to claim 1 wherein the component (b) is a material of the group consisting of polyethylene glycol sorbitan monooleate and polyethylene glycol stearate, and the fat (c) is a material of the group consisting of peanut oil, soya bean oil, grape seed oil, castor oil, olive oil, coconut oil, fish oil, cocoa-butter, and coconut butter.

8. The method according to claim 7 wherein said fat is peanut oil.

9. The method according to claim 7 wherein said composition contains also a preserving agent and a stabilizer.

References Cited UNITED STATES PATENTS 6 FOREIGN PATENTS 803,078 10/ 1958 Great Britain. 806,723 12/1958 Great Britain.

OTHER REFERENCES Atlas Sorbitol, published by Atlas Powder Co., Wilmington, Del., 1947, pages 16 and 17.

Grollman: J. Clinical Nutrition, vol. 1, pp. 302-5, 1953.

Shoshkes: Annals of the New York Academy of Sciences, vol. 56, Article 1, pages 22 to 25, Oct. 10, 1952.

Singleton et al.: Reprint from J. American Oil Chem ists Society, vol. 35, No. 6, pages 265 to 270, June 1958.

Speel: Reprint from The American Journal of Pharmacy, vol. 113, No. 4, page 5, April 1941.

LEWIS GOTTS, Primary Examiner.

RICHARD L. HUFF, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 ,340 ,151 September 5 1967 Sven Axel Eriksson et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 31, for "sorbital" read sorbitol column 3, line 52, for "soluble" read insoluble Signed and sealed this 3rd day of September 1968.

(SEAL) Attest:

EDWARD J. BRENNER Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer 

1. A METHOD OF CONTRACTING THE GALL BLADDER FOR X-RAY DIAGNOSIS WHICH COMPRISES ADMINISTERING ORALLY AN EFFECTIVE DOSE OF A COMPOSITION CONSISTING ESSENTIALLY OF, AS ITS ACTIVE CONSTITUENTS, (A) A MATERIAL OF THE GROUP CONSISTING OF SORBITOL AND MANNITOL, (B) A MATERIAL OF THE GROUP CONSISTING OF NONTOXIC WATER-DISPERSIBLE POLYETHYLENE GLYCOL ESTERS AND ETHERS CONTAINING AT LEAST ABOUT 5 OXYETHYLENE GROUPS PER MOLECULE, OF THE CLASS CONSISTING OF (1) POLYETHYLENE GLYCOL ESTERS OF HIGHER FATTY ACIDS, (2) POLYETHYLENE GLYCOL ETHERS OF HIGHER FATTY ALCOHOLS, AND (3) POLYOXYETHYLENE DERIVATIVES OF CYCLIZED HEXITOLS ESTERIFIED WITH HIGHER FATTY ACIDS, AND (C) A MATERIAL OF THE GROUP CONSISTING OF SOLID AND LIQUID ANIMAL AND VEGETABLE EDIBLE FATS, SAID CONSTITUENTS BEING DISPERSED IN WATER, SAID CONSTITUENTS BEING WITHIN THE LIMITS OF 10 TO 70 PARTS BY WEIGHT OF SORBITOL AND MANNITOL, 2 TO 15 PARTS BY WEIGHT OF SAID POLYETHYLENE GLYCOL ESTERS OR ETHERS, OR POLYOXYETHYLENE DERIVATIVES, AND 0.1 TO 1.5 PARTS BY WEIGHT OF THE FAT, PER 100 PARTS OF WATER. 